Cerebrovascular diseases such as cerebral apoplexy and cardiac infarction which rank high in the list of death causes in Japan are all caused by the sclerosis of the arteries.
Although hypolipidemic drugs which are effective in lowering the content of lipid, particularly cholesterol in the blood have been mainly used for the prevention and treatment of arteriosclerosis, no decisively effective drug has been found as yet.
Many studies have been made on arteriosclerosis and it has recently been found that an enzyme called ACAT (acyl-CoA: cholesterol O-acyl transferase) present in the arterial wall acts as an important factor in the formation of fat striae which are observed in arteriosclerosis (atherosclerosis).
That is, the formation of cholesterol ester on the arterial wall is catalyzed by the ACAT, so that an increase in the amount of the ACAT participates in the excess accumulation of cholesterol ester. Accordingly, it is expectable that the excess accumulation of cholesterol ester on the arterial wall may be controlled by the inhibition of the ACAT.
Meanwhile, the ACAT is also known to participate in the intestinal absorption of cholesterol. That is, dietary cholesterol and cholesterol discharged into the intestines by the adaptation of a living body itself in a state mixed with bile are absorbed as free cholesterol, esterified by the action of the ACAT, packed into chylomicrons and discharged into the blood. Accordingly, it is expectable that the intestinal absorption of cholesterol may be controlled by the inhibition of the ACAT in the intestines.
The inventors of the present invention have eagerly studied for many years on a compound which exhibits an inhibitory activity against the ACAT of the arterial wall and the intestines to thereby hinder the excess accumulation of cholesterol ester on the arterial wall and the intestinal absorption of cholesterol with their attentions being paid to the ACAT to find out that a benzene or pyrimidine derivative or a pharmacologically acceptable salt thereof can attain the object as will be described below.
Although compounds exhibiting an inhibitory activity against the ACAT have been proposed in, for example, U.S. Pat. Nos. 4,623,662, 4,489,094, 4,489,090, 4,824,843 and 4,285,951 and Japanese Patent Laid-Open Nos. 134070/1983, 231058/1984, 41655/1985, 277351/1987, 258366/1987, 23848/1988, 253060/1988, 19016/1989, 93569/1989, 203360/1989, 6455/1990, 6457/1990 and 6456/1990, the compounds of the present invention are different from them in the chemical structures.